聚集素在阿尔茨海默病早期诊断中的应用及机制初探

项目名称： 聚集素在阿尔茨海默病早期诊断中的应用及机制初探

项目编号： No.81200835

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 神经系统疾病、精神疾病

项目作者： 赵倩华

作者单位： 复旦大学

项目金额： 23万元

中文摘要： 本研究围绕聚集素蛋白，从临床研究和基础实验评价血浆聚集素在阿尔茨海默病早期诊断中的价值。从前期队列研究中产生的病例中选取遗忘型轻度认知损害患者150例及认知正常老人150例，完成标准化信息采集、神经心理测验及血标本留取，纵向随访，定期检测血浆聚集素水平，揭示AD型MCI阶段聚集素动态演变规律；体外实验以Aβ单体及寡聚体对原代培养的海马神经元进行干预，观察Aβ对聚集素的上调作用。通过PI3K特异性抑制剂干预，探索Aβ对聚集素的上调机制；体内实验，合成聚集素小干扰RNA，分别干预PS1/APP转基因小鼠和野生型小鼠，观察Aβ与聚集素的后续改变，分析二者之间的因果关联。本研究的前瞻性设计可为聚集素作为AD早期诊断标志的评价提供最直接的证据；对于进一步探索AD发病机制、快速高效识别AD型MCI从而制定恰当的治疗方案有重要的理论及实践意义。

中文关键词： 聚集素；beta淀粉样蛋白；阿尔茨海默病；APP/PS1转基因小鼠；轻度认知损害

英文摘要： The study will focus on the clusterin (CLU). We will evaluate the feasibility of plasma clusterin as the early biomarker of Alzheimer's disease (AD) via both population study and basic research. 150 amnestic mild cognitive impairment (aMCI) patients and 150 cognitively normal controls will be selected from an established cohort. Standardized clinical evaluation, neuropsychological assessment will be performed and their blood samples will be collected. Subjects will be longitudinally followed up annually for up to 3 years. The dynamic alteration of the plasma clusterin overtime will be characterized. In the in vitro basic research, the primary cultured hippocampal neurons will be treated by Aβ monomers and oligomers with or without PI3K specific antagonist wortmannin. After the assessment of clusterin and cell liability, the mechanism of up-regulation of clusterin by Aβ will be revealed. In the in vivo experiment, clusterin siRNA will be generated and administered to PS1/APP transgenic mice and wild type mice. After analysis of clusterin and Aβ, the causal relationship between clusterin and Aβ will be described. The prospective nature of the current study will provide most direct data for evaluation of clusterin as an early AD marker. In addition, the exploratory laboratory work is of great theoretical and practi

英文关键词： clusterin；beta amyloid；Alzheimer's disease；APP/PS1 transgenic mice；mild cognitive impairment